Liposomes can be used as effective drug delivery vehicles, and commercially available liposomal products have been developed for treatment of diseases including cancer (Barenholz, Y., Curr. Opin. in Colloid & Interface Sci. 6(1): 66-77 (2001)). A liposome is a vesicle including at least one phospholipid bilayer separating an interior aqueous phase from the external aqueous environment. A liposome is capable of carrying both hydrophobic cargo in the lipid bilayer and/or hydrophilic cargo in the aqueous core. Liposome size is usually in a range from 50 to 250 nm, which is particularly suitable for targeted delivery of chemotherapy agents to solid tumor sites via the enhanced permeability and retention of cancer tissues (the EPR effect) (Maeda, H., et al., J. Controlled Release. 65(1-2): 271 (2000)). The preferential accumulation of drug-containing liposomes at the tumor site via EPR provides a means for localizing the drug, improving drug efficacy, and reducing drug toxicity to normal cells or tissues. For example, Doxil™, an FDA-approved liposome product containing doxorubicin, has been shown to have reduced toxicity compared with the free drug (Martin, F. J., et al., “Clinical pharmacology and antitumor efficacy of DOXIL.” Medical Applications of Liposomes. Ed. D.D. Lasic. Amsterdam: Elsevier. 1998, pp 635-688).
However, the benefits of liposomal drug delivery vehicles are limited by drawbacks including liposome metabolism and excretion from the body, as well as a certain level of intrinsic toxicity and side effects due to systemic distribution and delivery. In particular, optimizing the release rate of liposomal drug is a difficult balancing act between in vivo half life and release. In general, leaky liposomes will make the encapsulated drug more available, but cause more risk in toxicity similar to the free drug. On the other hand, less leaky liposomes may reduce toxicity, but they may not provide the desirable drug release for efficacy as shown in a cisplatin preparation (SPI-077) (Kim, E. S. et al., Lung Cancer. 34(3): 427-432 (2001)). Therefore, balancing efficacy and safety in the development and administration of liposomal drug products constitutes a significant challenge.
Accordingly, there is a need to develop formulations and delivery methods which overcome the limitations of therapies based on singular liposomal preparations. The present invention addresses this and other needs, providing a means of improving drug safety and efficacy.